Modern Research on Black Cumin

Black Cumin (Nigella sativa) is a well known spice in the Middle East and India. Less familiar in the West, it is often confused with the more common cumin (Cuminum cyminum). Black cumin grows well in the Mediterranean region and in Western Asian countries including India, Pakistan and Afghanistan. It has a long history and is described in many ancient texts, including the Bible. Black cumin seeds were found in the tomb of the Egyptian Pharaoh Tutankhamen, and Hippocrates commented on its many benefits. In our own time, the results of modern research have begun to support a famous statement attributed to the Prophet Mohammad, referring to it “a remedy for every disease except death.”

In Ayurveda, black cumin is also called kalonji, upakuncika, karavi, and krishnajiraka. It is known to balance both Vata and Kapha, and increase Pitta. Its tastes are pungent and bitter, and it energetic action is heating. In both India and the Middle East it is traditionally used to help conditions such as: congestion, bronchitis, asthma, gastrointestinal problems, fever, woman’s health problems, eczema, pain, headaches, and to strengthen Agni.

While most of these papers have been animal or laboratory studies, a number of human studies have also been conducted. For example, in the area of respiratory disease, an early clinical study was done at Humboldt University in Berlin, Germany, in 2003, studying the effects of black cumin on 152 patients with allergic diseases (allergic rhinitis, bronchial asthma, atopic eczema). Improvements in symptoms were found across the board, with a slight decrease in plasma triglycerides and a discrete increase in HDL cholesterol, while the lymphocyte subpopulations, endogenous cortisol levels, and ACTH release remained unchanged (41).

Another human clinical study conducted in Indonesia was published in 2007 and examined the symptomatic treatment of acute tonsillo-pharyngitis in patients, using a combination of extract of black cumin with another herb called Phyllanthus niruri. The researchers found a significant benefit compared to a placebo in the treatment of acute tonsillo-pharyngitis (42). A study done in Iran, and published in 2007, examined the possible prophylactic effect of black cumin seed extract in asthmatic patients. Previous animal studies had demonstrated the relaxant, anticholinergic, and antihistaminic effects of black cumin. In this study, 29 asthmatic adults were divided into two groups and studied for 3 months. All symptoms in the group taking black cumin were significantly improved as compared to those of the control group. Also, the use of inhaler and oral beta-agonists, oral corticosteroid, and oral theophylline, decreased at the end of the study in the group using black cumin, while there were no obvious changes in the control subjects (43)

A second study done in Iran in 2008 examined the prophylactic effect of a boiled aqueous extract of black cumin seed on chemical war victims. Forty chemical war victims were randomly divided into a control group (taking a placebo daily) and study group (taking black cumin extract daily), and studied for 2 months. All respiratory symptoms, chest wheezing, and pulmonary function test values in the study group significantly improved in the second and third examination, compared to the first examination. Bythe third examination, all pulmonary functions test values, and most symptoms in the study group were significantly improved compared to those of the control group. In the control group, there were only small improvements in some parameters in the second and third visits. The use of inhaler and oral beta-agonists, and oral corticosteroids in the study group, decreased by the end of the study, while there were no obvious changes in use of these drugs in control subjects (44).

Finally, a third study by the same group in Iran was published in 2010. They examined the effect of two doses of boiled extract of black cumin upon the airways of 15 asthmatic patients. Results showed that the extract caused significant increases in all measured pulmonary function tests. The timing of the onset of the bronchodilatory effect of the extract was similar to that of theophylline, however the effects of both doses of the extract were significantly less than that of theophylline or salbutamol (45).

In the area of cardiovascular disease, a randomized, double-blind, placebo-controlled study in Iran was published in 2008 and investigated the use of black cumin in patients with mild hypertension. Subjects were randomized into three groups: a placebo group, and two test groups which received 100 and 200 mg of black cumin extract twice a day. After 8 weeks, systolic and diastolic blood pressure values in all three case groups were found to be significantly reduced when compared with the baseline values for each group, and statistically reduced compared to the placebo group. Black cumin extract also caused a significant decline in the level of total and low-density-lipoprotein (LDL)-cholesterol (46). In another study conducted in Pakistan a year later, 123 people were recruited for a randomized, double-blind controlled trial. This study examined serum lipid levels, blood sugar, blood pressure, and body weight, with the use of black cumin. Only 71 of the subjects completed the study and the results did not show significantly different changes from controls, even though there was an improvement in almost all variables. The authors recommend that a larger study be conducted with an adequate sample size (47).

In two other studies conducted in Pakistan, patients taking black cumin showed significant improvement in both cholesterol and lipid level (48,49). A clinical study done at Isfahan University of Medical Sciences, Isfahan, Iran, and published in 2012, examined the effects of black cumin on hypercholesterolemia in a randomized, placebo-controlled clinical trial involving some 88 subjects. The results showed a decrease in total cholesterol, low-density lipoprotein and triglycerides (50). Several articles have reviewed the various effects of black cumin on hypertension and cardiovascular disease, and commented that its cardiovascular protective effects may be due to its multiple actions as: an antioxidant, a cardiac depressant, a diuretic, and a calcium channel blocker (51, 52).

The anti-diabetic properties of black cumin have been studied extensively in animals but not in humans (40). However, there have been related studies. For example, a well controlled study conducted in Indonesia and published in 2010, studied the effects of black cumin on testosterone levels and metabolic disturbances in obese men. The results showed that in a comparison between the treatment group using black cumin and the control group using a placebo, there was a very significant reduction in body weight and waist circumference, but an insignificant reduction of serum free testosterone, and systolic and diastolic blood pressure (53). In another study published in 2008 and conducted in North India, 60 patients who met specific criteria for insulin resistance syndrome were divided into two groups. The control group took 10 mg of atorvastatin once a day and 500 mg of metformin (both in tablet form) twice a day, for a period of 6 weeks. The experimental group patients took 10 mg of atorvastatin once a day, and 500 mg of metformin (both in tablet form) twice a day, and 2.5 ml of black cumin oil twice daily, for a period of 6 weeks. The treatment group showed significant improvement with reference to total cholesterol, low-density lipoprotein cholesterol, and fasting blood glucose. Researchers concluded that black cumin was effective as an add-on therapy in patients with insulin resistance syndrome, and has significant activity in diabetic and dyslipidemic patients (54).

In a study done at King Saud University in Riyadh, Saudi Arabia, and published in 2010, the effects of black cumin was examined on the metabolic activities of the enzymes and genes CYP3A4 and CYP2D6, which are part of cytochrome P450 system and involved in liver detoxification. Black cumin significantly inhibited CYP2D6 and CYP3A4 mediated metabolism of dextromethorphan in human liver microsomes and in healthy human volunteers (55).

Early research showed the positive effects of black cumin in an animal model of rheumatoid arthritis (56). More recently, a study done in Egypt in 2012 was a placebo-controlled design, which investigated the effects of black cumin on 40 female patients with rheumatoid arthritis. A significant improvement in a number of clinical measures used to evaluate the symptoms of rheumatoid arthritis was found with the use of black cumin as compared to a placebo (57).

Recent research done in 2011 in Iran, examined the effects of thymoquinone extracted from black cumin on intractable pediatric seizures in a double-blinded crossover clinical trial study. A significant reduction of frequency of seizures in comparison with the control group was found (58). Another study conducted in 2013, looked at the effects of black cumin on cognitive functions. Previous studies had shown the neuroprotective effects of black cumin on animals (59), and this study demonstrated its role in enhancing memory, attention and cognition in humans. The authors suggest that it could be considered as potential food supplement for preventing or slow progressing of Alzheimer disease (60). Finally, a study done in 2008 in Pakistan, investigated the effects of black cumin on 35 addicts and found that is effective in long-term treatment of opioid dependence, also curing the infections from which majority of addicts suffer (61).

Black Cumin and Cancer

Past research has identified a number of spices and herbs as potential anti-cancer agents including: turmeric (curcumin), red chilli (capsaicin), cloves (eugenol), ginger (zerumbone), fennel (anethole), kokum (gambogic acid), fenugreek (diosgenin), and black cumin (thymoquinone) (62). PudMed lists over 100 papers on the effects of black cumin and its principle active ingredient, thymoquinone, against a wide range of different cancers, including breast, pancreatic, colon, prostate, and even liver, lung, and brain cancers.

Among the first studies were those from the Amala Research Center in Trichur, India, which reported in 1989 the use of black seed oil as a potential anticancer agent (63-65). In the US, similar findings were obtained by the Cancer Research Facility at Hilton Head Island, South Carolina, and at the Natural Products Chemistry laboratory in Lexington, Kentucky (66). Other laboratories in Egypt and Singapore were also studying the effects of black cumin on cancer (67- 69). More and more studies continued to be published, and report the anti-cancer effects of black cumin on different types of cancer. For example, a study in 2003 at Jackson State University in Florida, found black cumin effective against breast cancer cells, and another study in 2005 in Ireland, showed its effectiveness against lung cancer, cancer of the larynx, colon cancer, and pancreatic cancer cell lines (70, 71). Researchers at the Henry Ford Hospital in Michigan looked more closely at the mechanism involved, and observed that thymoquinone was able to inhibit DNA synthesis, proliferation, and viability of cancerous cells, but not noncancerous prostate cells, by suppressing specific gene expression (72). Further studies on the effects of black cumin on prostate cancer indicate that at low dosage, thymoquinone inhibits tumor angiogenesis and human prostate tumor growth with almost no chemotoxic side effects (73).

In the US, a study in 2009 showed that thymoquinone increased the effectiveness of chemotherapeutic agents in the killing of pancreatic cells, again by affecting specific gene expression. In another study the same year, thymoquinone was shown to induced apoptosis (preprogrammed cell death) and inhibited proliferation in pancreatic cancer cells (74,75). In 2010, a paper was published on a study conducted in Tanta, Egypt, on the use of black cumin against colon cancer in rats, and it was found to greatly reduce the size of the colon tumors; it also reduced tumors in the lungs and alimentary canals (76). Another study in 2010, showed that black cumin could stop cancer cellular proliferation in multiple organ sites, including colon, lung, and esophageal tumors, with no evidence of clinical side effects (77).

Studies in Egypt have shown that bee honey mixed with black cumin induces apoptosis in liver cancer cells and improves their antioxidant status (78). A 2010 study conducted at the Alexandria University in Egypt, found marked improvements when conventional chemotherapy was combined with herbal therapy (using black cumin among other herbs) on the incidence of side effects of chemotherapy in 2nd stage breast cancer patients (79). A more recent study published in 2013, revealed that black cumin induces apoptosis in cervical cancer cells through activation of specific enzymes (80).

Biological Mechanism

Many active pharmacologically important ingredients have been found in black cumin, including thymoquinone, dithymoquinone, thymohydroquinone, and thymol. Thymoquinone is the most well studied component, and is considered to be the active ingredient with many different effects. It is a relatively safe compound, particularly when given orally (81-83).

Thymoquinone acts as an anticancer and anti-inflammatory agent in a number of different ways. An excellent review by Khan and coworkers suggests that it induces apoptotic cell death in cancerous tissues by upregulating the expression of apoptotic genes (caspases and bax), and down-regulating the expression of anti-apoptotic genes (e.g.,bcl 2); it suppresses Akt activation by dephosphorylation and thus blocks cancer cell survival; it deactivates the important NFkappa B pathway, which is key to promoting inflammation and cancer; and it increases the activities of antioxidant enzymes and protects cell against cancer. In addition, it protects against normal cell injury that can be caused by the ionizing radiation used in some cancer treatments. It also has a hepatoprotective role, which is helpful in cancer prevention and treatment (84). These same anti-cancer mechanisms of thymoquinone have also been reviewed in several other papers (85-87). One of these papers reviewed the effects of thymoquinone combined with conventional chemotherapeutic drugs and found that the combination could produce greater therapeutic effect, as well as reduce the toxicity of the drugs (87).

In another study in India published in 2013, investigators found that thymoquinone targets cellular copper in prostate cancer cell lines, leading to a prooxidant cell death. They believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants (88). Researchers at Tulane University School of Medicine in New Orleans published a study in 2010 on the molecular mechanisms involved in thymoquinone induced cell death, showing that it is primarily due to increased reactive oxygen species generation and decreased glutathione levels, and is independent of androgen receptor activity (89). Another study conducted and published by the Anderson Cancer Center in Houston in 2010, demonstrated that encapsulation of thymoquinone into nanoparticles enhances its anti-proliferative, anti-inflammatory, and chemosensitizing effects (90).

Finally, a recent paper published in 2013 from research conducted at the University of Toyama in Japan, examined the effect of black cumin on inducible nitric oxide synthase enzyme activity, which has been implicated in the growth of various tumors. It was found that black cumin attenuated the inducible nitric oxide synthase pathway and suppressed the inflammatory response mediated by tumor necrosis factor-α and interleukin-6, again suggesting black cumin’s role as a natural and effective anticancer and anti-inflammatory agent (91).